PL120041B1 - Process for preparing novel derivatives of cyclodecane - Google Patents
Process for preparing novel derivatives of cyclodecane Download PDFInfo
- Publication number
- PL120041B1 PL120041B1 PL1979220531A PL22053179A PL120041B1 PL 120041 B1 PL120041 B1 PL 120041B1 PL 1979220531 A PL1979220531 A PL 1979220531A PL 22053179 A PL22053179 A PL 22053179A PL 120041 B1 PL120041 B1 PL 120041B1
- Authority
- PL
- Poland
- Prior art keywords
- carbon atoms
- condensing agent
- alkali metal
- compound
- general formula
- Prior art date
Links
- 238000004519 manufacturing process Methods 0.000 title description 2
- LMGZGXSXHCMSAA-UHFFFAOYSA-N cyclodecane Chemical class C1CCCCCCCCC1 LMGZGXSXHCMSAA-UHFFFAOYSA-N 0.000 title 1
- 125000004432 carbon atom Chemical group C* 0.000 claims description 37
- 150000001875 compounds Chemical class 0.000 claims description 34
- 238000000034 method Methods 0.000 claims description 32
- 239000003795 chemical substances by application Substances 0.000 claims description 19
- 125000000217 alkyl group Chemical group 0.000 claims description 14
- 150000003839 salts Chemical class 0.000 claims description 13
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 12
- 239000002253 acid Substances 0.000 claims description 12
- -1 alkali metal alkoxide Chemical class 0.000 claims description 11
- 125000002947 alkylene group Chemical group 0.000 claims description 9
- 229910052757 nitrogen Inorganic materials 0.000 claims description 7
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 7
- 229910052760 oxygen Inorganic materials 0.000 claims description 7
- 239000001301 oxygen Substances 0.000 claims description 7
- 125000001453 quaternary ammonium group Chemical group 0.000 claims description 7
- 229910052717 sulfur Inorganic materials 0.000 claims description 7
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 6
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 5
- 238000006243 chemical reaction Methods 0.000 claims description 5
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 5
- 125000005842 heteroatom Chemical group 0.000 claims description 5
- 125000000623 heterocyclic group Chemical group 0.000 claims description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 5
- 150000007530 organic bases Chemical class 0.000 claims description 5
- 239000011593 sulfur Substances 0.000 claims description 5
- DDTBPAQBQHZRDW-UHFFFAOYSA-N cyclododecane Chemical class C1CCCCCCCCCCC1 DDTBPAQBQHZRDW-UHFFFAOYSA-N 0.000 claims description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 3
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 3
- 125000004429 atom Chemical group 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 125000004434 sulfur atom Chemical group 0.000 claims description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims 8
- 229910052783 alkali metal Inorganic materials 0.000 claims 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims 4
- 229910000102 alkali metal hydride Inorganic materials 0.000 claims 4
- 150000008046 alkali metal hydrides Chemical class 0.000 claims 4
- 239000002585 base Substances 0.000 claims 4
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 claims 4
- 229910000104 sodium hydride Inorganic materials 0.000 claims 4
- 239000012312 sodium hydride Substances 0.000 claims 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims 3
- 239000012442 inert solvent Substances 0.000 claims 2
- 125000004430 oxygen atom Chemical group O* 0.000 claims 2
- 238000007259 addition reaction Methods 0.000 claims 1
- 229910001514 alkali metal chloride Inorganic materials 0.000 claims 1
- 150000001340 alkali metals Chemical class 0.000 claims 1
- 125000003282 alkyl amino group Chemical group 0.000 claims 1
- 238000010791 quenching Methods 0.000 claims 1
- 230000000171 quenching effect Effects 0.000 claims 1
- 125000000547 substituted alkyl group Chemical group 0.000 claims 1
- 239000000203 mixture Substances 0.000 description 9
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 8
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000013543 active substance Substances 0.000 description 6
- 229920002261 Corn starch Polymers 0.000 description 5
- 239000008120 corn starch Substances 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 4
- 235000019359 magnesium stearate Nutrition 0.000 description 4
- XQYZDYMELSJDRZ-UHFFFAOYSA-N papaverine Chemical compound C1=C(OC)C(OC)=CC=C1CC1=NC=CC2=CC(OC)=C(OC)C=C12 XQYZDYMELSJDRZ-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000007903 gelatin capsule Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 239000000454 talc Substances 0.000 description 3
- 229910052623 talc Inorganic materials 0.000 description 3
- 231100001274 therapeutic index Toxicity 0.000 description 3
- SNICXCGAKADSCV-JTQLQIEISA-N (-)-Nicotine Chemical compound CN1CCC[C@H]1C1=CC=CN=C1 SNICXCGAKADSCV-JTQLQIEISA-N 0.000 description 2
- 229930008281 A03AD01 - Papaverine Natural products 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- RWGFKTVRMDUZSP-UHFFFAOYSA-N cumene Chemical compound CC(C)C1=CC=CC=C1 RWGFKTVRMDUZSP-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 239000008298 dragée Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 239000003589 local anesthetic agent Substances 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 229960002715 nicotine Drugs 0.000 description 2
- SNICXCGAKADSCV-UHFFFAOYSA-N nicotine Natural products CN1CCCC1C1=CC=CN=C1 SNICXCGAKADSCV-UHFFFAOYSA-N 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- 229960001789 papaverine Drugs 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 description 1
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 1
- 229910002012 Aerosil® Inorganic materials 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 230000003444 anaesthetic effect Effects 0.000 description 1
- 230000003288 anthiarrhythmic effect Effects 0.000 description 1
- 229940124599 anti-inflammatory drug Drugs 0.000 description 1
- 230000000794 anti-serotonin Effects 0.000 description 1
- 239000003416 antiarrhythmic agent Substances 0.000 description 1
- 239000003420 antiserotonin agent Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- OSBIGBJYJFOYGK-UHFFFAOYSA-N cyclododecane hydrochloride Chemical compound C1CCCCCCCCCCC1.Cl OSBIGBJYJFOYGK-UHFFFAOYSA-N 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 239000004744 fabric Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 210000003405 ileum Anatomy 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 231100000225 lethality Toxicity 0.000 description 1
- 229960005015 local anesthetics Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 230000007721 medicinal effect Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 208000022084 motor paralysis Diseases 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 230000002048 spasmolytic effect Effects 0.000 description 1
- 239000004575 stone Substances 0.000 description 1
- 239000007916 tablet composition Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 231100000816 toxic dose Toxicity 0.000 description 1
- QDWJJTJNXAKQKD-UHFFFAOYSA-N trihexyphenidyl hydrochloride Chemical compound Cl.C1CCCCC1C(C=1C=CC=CC=1)(O)CCN1CCCCC1 QDWJJTJNXAKQKD-UHFFFAOYSA-N 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- Neurology (AREA)
- General Health & Medical Sciences (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Physical Education & Sports Medicine (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Steroid Compounds (AREA)
Description
Przedmiotem wynalazku jest laposólb wytwarza¬ nia nowych pochodnych cyklododeikanu o wzorze ogólnym 1, ich optycznie czynnych izomerów, so¬ li addycyjnych z kwasami i czwartorzedowych so¬ li amoniowych, posiadajacych cenne wlasciwosci lecznicze i stosowanych jako aktywny skladnik w kompozycjach farmaceutycznych.Wedlug wynalazku zwiazek o wzorze ogólnym 1, w którym R1 i R2 niezaleznie od siebie oznacza¬ ja atomy wodoru, grupy alkilowe o 1—6 ato¬ mach wegla, lub grupy cykloalkilowe o 3—8 ato¬ mach /wegla, albo tez R1 i R2, wraz z atomem azotu, z którym sa polaczone tworza pierscien heterocykliczny zawierajacy 4—7 atomów wegla i ewentualnie dodaitjkowy heteroatom, talki jak a- tom tlenu, siarki lub aizotu, przy czym pierscien ten moze byc ewentualnie podstawiony grupa al¬ kilowa o (1h-3 atomach wegla lub girupa benzylo¬ wa, symbol A oznacza pirosty lub rozgaleziony lancuch alkilenowy zawierajacy od 2 do 6 atomów wegla wyitwarza' sie przez reakcje pochodnej cy¬ klododekanu o wzorze ogólnym 2, w którym Y oznacza atom tlenu lub siarki albo grupe =N-^OH, z pochodna aminoalkilowa o ogólnym wzorze 3, w którym X oznacza atom chlorowca albo grupe H2N*—O—, a R1 i R2 maja podane, wyzej znacze¬ nie, w obecnosci zasadowego srodka kondensuja- cego.Zwiazki o wzorze ogólnym 2 sa produktami do¬ lo 15 20 2 stepnymi w handlu, lub mozna je wytwarzac zna¬ nym sposobem (Helv. Ohim. Acta t. 132 1049, s 544—652).Zwiazki o wzorze ogólnym 3, w .których X oznacza atom chlorowca, sa znane i dostepne w handlu.Zwiazki o wzorze ogólnym 3, w których X o- znacza grupe H21N—O— wytwarza sie sposobem opisanym w J. Pharm. Sci. t. 58, 138^140 (1909).Reakcje zwiazków o wzorach ogólnych 2 i 3 prowadzi sie w rozpuszczalniku chemicznie obo¬ jetnym w stosunku do reagentów lub w miesza¬ ninie takich rozpuszczalników. Do obojetnych roz¬ puszczalników naleza np. alkohole, takie-jak eta¬ nol oraz pirydyna, trójetyloamina, benzen i jego homologi, takie jak toluen, ksylen, kumen ftp. e- tery takie jak czterowodorofuran i eter butylo¬ wy, dwumetyloformainiid, a takze jmieszaniny tych rozpuszczalników.W reakcji zwiazków o wzorach ogólnych 2 i 3 stosuje sie zasadowy srodek kondensujacy. W za¬ leznosci od charakteru grupy X i Y jako sroidiek kondensujacy stosuje sie metal alkaliczny, ko¬ rzystnie sód* amidek metalu alkalicznego, korzyst¬ nie amidek sodowy, wodorek metalu alkalicznego, korzystnie woidorek sodowy, alkoholan metalu al¬ kalicznego, korzystnie metanolan sodu, albo zasa¬ dy organiczne, korzystnie takie pirydyna, pikolina, trójetyloamina itp. 120 041120 041 Reakcje (prowadzi (Sie w Szerokim zakresie tem¬ peratur, od 30—40°C do temperatury wrzenia sto¬ sowanego rozpuszczalnika,, korzystnie w tempera¬ turze (w zakresie od 70 do <130°C.Zwiazki o wzorze ogólnym I wytworzone spo¬ sobem wedlug wynalazku mozna w frazie potrzeby przeksztalcac znanym sposobem w leczniczo do¬ puszczalna sól addycyjna z ikwasem lub czwarto¬ rzedowa pochodna amoniowa. Do wytwarzania takich soli addycyjnych stosuje sie np. kwasy cMorowcowodorowe, kwas siarkowy, maleinowy, fosforowy, cytrynowy, winowy, fumarowy, octo¬ wy, propionowy, metanosulfonowy istp. W celu wytworzenia czwartorzedowych zwiazków amo¬ niowych zwiazki o wzorze ogóllnym i poddaje sie reakcji z halogenkami alkilowyimi lub estrami kwasiu metanosulfonowego, nadajacymi sie do wy¬ twarzania takich zwiazków czwartorzedowych.Mieszaniny racemiczne zwiazków o wzorze o- gólnym 1 rozdziela sie na odpowiednie optycznie czynne izomery znanymi sposobami, np. iprzez kry¬ stalizacje frakcjonowana, W czasie badan zwiazków o wzorze ogólnym 1 stwierdzono, ze sa one biologicznie czynne w sze¬ regu testach. Do najwazniejszych przejawów ak¬ tywnosci biologicznej nalezy dzialanie spazmoli- tyczne, dzialanie miejscowo znieczulajace oraz dzialanie opózniajace .smiertelnosc nikotynowa, uzupelniane przez dzialanie przeciwarytmiczne i przeciwserotoninowe.Dzialanie opózniajace imierc nikotynowa oba¬ dano na myszach imetoda Stone'a {O. A. Stone i in,: Arch. Intern. Pharmacodynamic t. 117, 419 (li958)), w grupach po 10 zwierzat, przy dodawa¬ niu doustnym. Dawki toksyczne wyznaczono rów¬ niez przy podawaniu doustnym.Wartosci LD50 zawarte w tablicy 1 oznaczaja dawki, przy których ginie 50M badanych zwierzat, natomiast wartosci ED^o oznaczaja dawki, przy których u 50!% badanych zwierzat mozaia zaobser¬ wowac skuteczne dzialanie farmakologiczne.Wskaznik terapeutyczny aest wartoscia otrzymana przez podzielenie LDie przoz Elfyo i Ó€st propor^ cjonalny do skutecznosci farmakologicznej bada¬ nych zwiazków w tablicy 1 podano idla porówna¬ nia odpowiednie wartosci dla leku znanego pod nazwa Artane.Tablica 1 Wskaznik terapeutyczny ED50 Zwiazek I IV vn 11 1 v 1 1-cyklonek- sylo-l-fe- nylo-3-pi- perydyno- ipropanol-1 (Artaoe) Crng/kg] 360 680 1100 780 B00 365 ED50 [mg^] 139 w w w 40 Wskaznik terapeu¬ tyczny W4 14,8 m «,w 1 10 15 20 25 30 40 50 55 Dzialanie spazanolityczne na miesien gladki zba¬ dano na izolowanym jelicie kretym szczura zgod¬ nie z metoda Brock'a i in. H. Brock, J. Ceks, D. Lorenz: Arch. Expex. Pa 2115, 49(2 (1:9152), stosuijac papaweryne jako substan¬ cje wzorcowa. W celu okreslenia skutecznosci po¬ szczególnych zwiazków ich wzgledny efekt w sto¬ sunku ido papaweryny zestawiono w ponizszej ta¬ blicy 2.Tablica 2 Zwiazek (nr przykladu) I IV II V VI XI X Papaweryna Wzgledna skutecznosc ¦1,4 4,1 1,6 1,7 0,'9 •2,6 2,'9 1,0 Dzialanie miejscowo znieczulajace zbadano na nerwie kulszowym (N. ischiatious) szczurów meto¬ da Truanfa A. P. Truant, d^Amato, cytowani w pracy A. P. Truant, S. Wiedling: Acta Chirurg.Scand. t. 1)16, 351 (H9I58), stosujac fcsylokaine jako substancje wzorcowa. Wyznaczono ilosc zwierzat wykazujacych charakterystyczne porazenie moto- ryczne oraz czas trwania tego zjawiska. Wzgjetfna skutecznosc w stosunku do Kisylokainy oraz czas trwania zjawiska zaobserwowany przy podaniu zwiaziku w stezeniu 0#5P/o i 0;5°/o podano w.tabli¬ cy 3.Tablica S Zwiazek (nr {przy¬ kladu) I IV II V VI XI X XII Ksylokaina Wzgledna skutecz-r nosc 0,77 0,63 0,67 0,71 O.y'50- 1,86 2,00 1,68 1,0 Czas trwania zjawiska 1 minuty 0,25% 45 212 23 31 60 151 76 77 24 0,5% 95 105 57 60 134 240 104 240 28 65 Wzgledna skutecznosc =" EC50 !('Z)wiazelk wzorcowy) EC50 (zwiazek badany)a 180 Otl 6 Zwiazki o wzoiree -Ogólnym lv orrifc ich farmaceu¬ tycznie dopuszczakie sole addycyjne z kwasami lub czwartorzedowe pochodnie amoniowe przetwa¬ rza sie znanymi sposobami na leki miejscowo znieczulajace, przecie chorobie Parkinsona i prae- ciWatytmiczne, stasiujac nosniki i/lub inne mate¬ rialy pomocnicze zazwyczaj stosowane -to produk¬ cji leków. Pojedyncza dawka kompozycji farma¬ ceutycznej zawiera zazwyczaj od 1 do 500 mg zwiazku o wzorze ogólnym i wytwarzanego spo¬ sobem wedlug wynalazku, jego soli addycyjnej z kwasem lufo czwartorzedowej pochodnej amonio¬ wej.Preparaty farmaceutyczne imozna wytworzyc wedlug nizej ,podanych sposobów: Taibletki zawierajace po 25 ang woderofumaranu l.-/dwaimetyloa^inopro^ Sklad tabletki: substancja aktywna Ibfl ntg ' : skrobia kukurydziana 97,0 img poliwkiylopirolidon 175ft mg stearynian (magnezowy 3,0 (300,0 img Po zwilzeniu 10—illp/t •wodnymi roztworem poili- wittylopiroliidóotl mieszanine aktyW-rtej su/bstancji i skrobi kukurydzianej granulowano, a nastepnie wysuszono w temperaturze 40^45°C Po powtór¬ nym wysuszeniu goranukt wymieszano ze steary¬ nianem (magnezowym i sprasowano na tabletki.Waga .tabletki Wynosi 900 mig.Drazetki zawierajace po i5 img Wodoiroiuma^a- Sklad' w rdzeniu drazetki: suibstancjn aktywna 25,0 mig skrobia kukurydziana 24/5,0 mg zelatyna ®fl img talk 18,0 mg stearynian magnezowy 4,0 mg 300,0 img Mieszanine substancji aktywnej i skrobi kuku¬ rydzianej zwilzono W/o wodnym roztworem zela¬ tyny, zgranulowano przepuszczajac przez flito i wysuszono w temperaturze 40—4/5°C. Suche po¬ wtórnie przetarto przez sito, wymieszano doklad¬ nie z talkiem i stearynianem magnezowym i na koniec sprasowano na rdzenie drazetek o wadie 300 mg kazdy. iDrazetki zawierajace <50 mg wodoroflumairanu l- Vdwuizopropyloa^inofcr mi.Sklad rdzenia drazetki: substancja aktywna i50,0 mg laktoza 07,0 mg poliwinylopirolidon (2,0 mg stearynian magnezowy 1,0 mg meritom spozywczym na odpowiedni kolor i Wy¬ polerowano Kapsulki zelatynowe zawierajace 25 mg woojo- rofumafraniu iWdwuetyloaininoetoksyimino/cyki^do- dekanu. Sklad kapsulki zelatynowej: substancja aktywna 25,0 mg skrobia kukurydziana 895,0 mg aerosil 6^)< mg istearynian (magnezowy 4,0 img 160/) im® •Granulat wytworzono sposofbeni rWediug powyz¬ szego przykladu, ildfcenie drazetek pokryto zna¬ nym sposobem wairstwA skladajac^ sie z cukru i talku. Drazetki zabarwiono nietoksycznym pig- 300,0 mg Skladniki zhomogehizowano, po czym mieszan¬ ka napelniono kapsulki zelatynowe odpowiedniej w Wielkosci.Itozitwoir do zastrzyków zawierajacy 23 mg wo* dorolumaranu i^wumetyloaminopro^oiksyimino/ /cyklódodekanu. Ampulka zawiera 2l5,0 mg aktyw¬ nego skladnika i 5 ml dwukrotnie destylowanej Ig wody.Wynalazek ilustruja nastepujace przyk&dy ±ite ograniczajace dego zakresu.Przyklad I. l-/dwumetyloammoip^^ PL PL The subject of the invention is a method of preparing new cyclododeicane derivatives of the general formula 1, their optically active isomers, acid addition salts and quaternary ammonium salts, having valuable medicinal properties and used as an active ingredient in pharmaceutical compositions. According to the invention, a compound with general formula 1, in which R1 and R2 independently of each other represent hydrogen atoms, alkyl groups with 1-6 carbon atoms, or cycloalkyl groups with 3-8 carbon atoms, or also R1 and R2, together with nitrogen atom, with which they are connected, they form a heterocyclic ring containing 4-7 carbon atoms and optionally an additional heteroatom, such as an oxygen, sulfur or nitrogen atom, and this ring may be optionally substituted with an alkyl group with (1h-3 atoms carbon or benzyl group, the symbol A means pyrostates or a branched alkylene chain containing from 2 to 6 carbon atoms is prepared by the reaction of a cyclododecane derivative of the general formula 2, in which Y is an oxygen or sulfur atom or a group =N-^ OH, with an aminoalkyl derivative of the general formula 3, wherein dolo products are commercially available, or they can be prepared by a known method (Helv. Ohim. Acta vol. 132 1049, pp. 544-652). Compounds of the general formula 3, in which X is a halogen atom, are known and commercially available. Compounds of the general formula 3, in which X is the group H21N-O- is prepared by the method described in J. Pharm. Sci. vol. 58, 138-140 (1909). The reactions of compounds of general formulas 2 and 3 are carried out in a solvent chemically neutral in relation to the reagents or in a mixture of such solvents. Neutral solvents include, for example, alcohols such as ethanol and pyridine, triethylamine, benzene and its homologues such as toluene, xylene, cumene ftp. ethers such as tetrahydrofuran and butyl ether, dimethylformainide, as well as mixtures of these solvents. In the reaction of compounds of general formulas 2 and 3, a basic condensing agent is used. Depending on the nature of the groups , or organic bases, preferably pyridine, picoline, triethylamine, etc. 120 041120 041 Reactions (carried out in a wide temperature range, from 30-40°C to the boiling point of the solvent used, preferably at ture (in the range from 70 to <130°C. The compounds of the general formula I prepared according to the invention can, if necessary, be converted in a known manner into a medicinally acceptable acid addition salt or a quaternary ammonium derivative. For the preparation of such salts addition acids are used, for example, hydrogen acids, sulfuric acid, maleic acid, phosphoric acid, citric acid, tartaric acid, fumaric acid, acetic acid, propionic acid, methanesulfonic acid, etc. In order to prepare quaternary ammonium compounds, compounds of the general formula and are reacted with alkyl halides or methanesulfonic acid esters, suitable for the preparation of such quaternary compounds. Racemic mixtures of compounds of general formula 1 are separated into the appropriate optically active isomers by known methods, e.g. by fractional crystallization. During the tests of compounds of general formula 1, it was found that they are biologically active in a number of tests. The most important manifestations of biological activity include a spasmolytic effect, a local anesthetic effect and a delaying effect on nicotine lethality, supplemented by an antiarrhythmic and antiserotonin effect. The delaying effect on nicotine death was tested in mice using Stone's method {O. A. Stone et al.: Arch. Internship Pharmacodynamic vol. 117, 419 (li958)), in groups of 10 animals, when administered orally. Toxic doses were also determined for oral administration. The LD50 values included in Table 1 indicate the doses at which 50 million of the tested animals die, while the ED20 values indicate the doses at which an effective pharmacological effect could be observed in 50% of the tested animals. The therapeutic index a is the value obtained by dividing the LDie by Elfyo and the sixth proportional to the pharmacological effectiveness of the tested compounds. Table 1 shows and for comparison the corresponding values for the drug known as Artane. Table 1 Therapeutic index ED50 Compound I IV vn 11 1 v 1 1-cyclonexyl-1-phenyl-3-pi- peridine- ipropanol-1 (Artaoe) Crng/kg] 360 680 1100 780 B00 365 ED50 [mg^] 139 w w w 40 Therapeutic index W4 14.8 m«,w 1 10 15 20 25 30 40 50 55 The spasanolytic effect on smooth muscle was tested on isolated rat ileum according to the method of Brock et al. H. Brock, J. Ceks, D. Lorenz: Arch. Expex. Pa 2115, 49(2 (1:9152), using papaverine as a standard substance. In order to determine the effectiveness of individual compounds, their relative effect in relation to papaverine is presented in Table 2 below. Table 2 Compound (No. example) I IV II V VI XI ischiatious) rats using the Truanf method of A. P. Truant, d^Amato, cited in the work of A. P. Truant, S. Wiedling: Acta Chirurg. Scand. vol. 1) 16, 351 (H9I58), using physylcaine as a standard substance. The number of animals showing characteristic motor paralysis and the duration of this phenomenon were determined. The relative effectiveness in relation to Kisylocaine and the duration of the phenomenon observed when the compound was administered at concentrations of 0% 5P/o and 0;5°/o are given in Table 3. Table S Compound (example no.) I IV II V VI XI X XII 23 31 60 151 76 77 24 0.5% 95 105 57 60 134 240 104 240 28 65 Relative effectiveness =" EC50 !('Z)reference compound) EC50 (test compound)a 180 Otl 6 Compounds with formulae -General lv orrifc their pharmaceutically acceptable acid addition salts or quaternary ammonium derivatives are processed by known methods into local anesthetics, Parkinson's disease and anti-inflammatory drugs, using carriers and/or other auxiliary materials commonly used in the production of drugs. A single dose of a pharmaceutical composition usually contains from 1 to 500 mg of the compound of the general formula and prepared according to the method of the invention, its acid addition salt or a quaternary ammonium derivative. Pharmaceutical preparations can be prepared according to the following methods: Tablets containing after 25 ang of 1-(dimethylaminopropyl) hydrogen fumarate Tablet composition: active substance Ibfl ntg': corn starch 97.0 img polyvinylpyrrolidone 175 ft mg stearate (magnesium 3.0 (300.0 img) After moistening with 10 with a solution of polyvinylpyrrolide, the mixture of active substance and corn starch was granulated and then dried at a temperature of 40-45°C. After drying again, the goranukt was mixed with stearate (magnesium stearate and pressed into tablets. The weight of the tablets is 900 mg Dragees containing 15 micrograms of water-soluble substance - Composition in the core of the dragee: active substance 25.0 mg, corn starch 24/5.0 mg, gelatin, fl img talc 18.0 mg, magnesium stearate 4.0 mg 300.0 img Mixture the active substance and corn starch were moistened with a water solution of gelatin, granulated by passing through a filter cloth and dried at a temperature of 40-4/5°C. The dry material was passed through a sieve again, mixed thoroughly with talc and magnesium stearate and finally pressed into tablet cores of 300 mg each. iDragettes containing <50 mg of l-diisopropyla^inofcr hydrogen flumairate. Composition of the core of the tablet: active substance i50.0 mg lactose 07.0 mg polyvinylpyrrolidone (2.0 mg magnesium stearate 1.0 mg food grades to the appropriate color and Polished Capsules gelatin capsules containing 25 mg of hydrofumafranium and diethyl ainine ethoxyimino/cyclides do-decane. Composition of the gelatin capsule: active substance 25.0 mg corn starch 895.0 mg aerosil 6^) < mg istearate (magnesium 4.0 img 160/) im® • The granules were prepared according to the above example, and the pellets were covered with a layer consisting of sugar and talc in a known manner. The tablets were colored with a non-toxic pigment. The ingredients were homogenized and then the mixture was filled into gelatin capsules of the appropriate size. Itozitwoir for injection containing 23 mg of hydrolumarate hydrochloric acid and cyclododecane hydrochloric acid. The ampoule contains 215.0 mg of the active ingredient and 5 ml of twice-distilled Ig water. The invention is illustrated by the following limiting examples. Example I. l-/dimethylammoip^^ PL PL
Claims (1)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU78EE2614A HU178518B (en) | 1978-12-19 | 1978-12-19 | Process for preparing cyclododekanone oxime ethers |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| PL220531A1 PL220531A1 (en) | 1980-08-25 |
| PL120041B1 true PL120041B1 (en) | 1982-02-27 |
Family
ID=10995810
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PL1979220531A PL120041B1 (en) | 1978-12-19 | 1979-12-19 | Process for preparing novel derivatives of cyclodecane |
Country Status (24)
| Country | Link |
|---|---|
| US (1) | US4285942A (en) |
| JP (1) | JPS55108847A (en) |
| AT (1) | AT372079B (en) |
| AU (1) | AU530721B2 (en) |
| BE (1) | BE880508A (en) |
| CA (1) | CA1123852A (en) |
| CH (1) | CH647755A5 (en) |
| CS (1) | CS209944B2 (en) |
| DD (1) | DD148216A5 (en) |
| DE (1) | DE2951235A1 (en) |
| DK (1) | DK541079A (en) |
| ES (1) | ES8100257A1 (en) |
| FI (1) | FI793964A (en) |
| FR (1) | FR2444666A1 (en) |
| GB (1) | GB2045744B (en) |
| GR (1) | GR74018B (en) |
| HU (1) | HU178518B (en) |
| IL (1) | IL58815A (en) |
| IT (1) | IT1220957B (en) |
| NL (1) | NL7909025A (en) |
| PL (1) | PL120041B1 (en) |
| SE (1) | SE7910430L (en) |
| SU (1) | SU833157A3 (en) |
| YU (2) | YU308479A (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| HU189226B (en) * | 1983-02-08 | 1986-06-30 | Egyt Gyogyszervegyeszeti Gyar,Hu | Process for producing basic oxime-ethers |
| HU212262B (en) * | 1992-10-30 | 1996-04-29 | Egyt Gyogyszervegyeszeti Gyar | Process to prepare benz /e/ indene derivs. and the pharmaceutical compns. contg. them |
| US5508302A (en) * | 1994-09-28 | 1996-04-16 | American Home Products Corporation | Phospholipase A2 inhibitors |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US1733462A (en) * | 1926-09-23 | 1929-10-29 | Winthrop Chem Co Inc | New basic oxime ethers of cyclic compounds |
| US4083978A (en) * | 1976-01-27 | 1978-04-11 | Egyt Gyogyszervegyeszeti Gyar | Oxime ethers |
-
1978
- 1978-12-19 HU HU78EE2614A patent/HU178518B/en not_active IP Right Cessation
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1979
- 1979-11-27 IL IL58815A patent/IL58815A/en unknown
- 1979-12-03 GR GR60658A patent/GR74018B/el unknown
- 1979-12-03 US US06/099,507 patent/US4285942A/en not_active Expired - Lifetime
- 1979-12-03 AT AT0765379A patent/AT372079B/en not_active IP Right Cessation
- 1979-12-07 CS CS798554A patent/CS209944B2/en unknown
- 1979-12-10 BE BE1/9638A patent/BE880508A/en not_active IP Right Cessation
- 1979-12-10 FR FR7930183A patent/FR2444666A1/en active Granted
- 1979-12-13 DD DD79217646A patent/DD148216A5/en unknown
- 1979-12-14 NL NL7909025A patent/NL7909025A/en not_active Application Discontinuation
- 1979-12-17 IT IT28029/79A patent/IT1220957B/en active
- 1979-12-17 YU YU03084/79A patent/YU308479A/en unknown
- 1979-12-18 SE SE7910430A patent/SE7910430L/en not_active Application Discontinuation
- 1979-12-18 SU SU792855002A patent/SU833157A3/en active
- 1979-12-18 DK DK541079A patent/DK541079A/en not_active Application Discontinuation
- 1979-12-18 AU AU53967/79A patent/AU530721B2/en not_active Ceased
- 1979-12-18 FI FI793964A patent/FI793964A/en not_active Application Discontinuation
- 1979-12-18 CH CH11197/79A patent/CH647755A5/en not_active IP Right Cessation
- 1979-12-18 GB GB7943550A patent/GB2045744B/en not_active Expired
- 1979-12-19 CA CA342,285A patent/CA1123852A/en not_active Expired
- 1979-12-19 DE DE19792951235 patent/DE2951235A1/en not_active Withdrawn
- 1979-12-19 ES ES487090A patent/ES8100257A1/en not_active Expired
- 1979-12-19 PL PL1979220531A patent/PL120041B1/en unknown
- 1979-12-19 JP JP16416379A patent/JPS55108847A/en active Pending
-
1983
- 1983-04-21 YU YU00912/83A patent/YU91283A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| GR74018B (en) | 1984-06-06 |
| JPS55108847A (en) | 1980-08-21 |
| AT372079B (en) | 1983-08-25 |
| IL58815A0 (en) | 1980-02-29 |
| DK541079A (en) | 1980-06-20 |
| IL58815A (en) | 1984-01-31 |
| FR2444666A1 (en) | 1980-07-18 |
| YU91283A (en) | 1983-12-31 |
| ES487090A0 (en) | 1980-11-01 |
| BE880508A (en) | 1980-06-10 |
| IT1220957B (en) | 1990-06-21 |
| HU178518B (en) | 1982-05-28 |
| DE2951235A1 (en) | 1980-11-06 |
| NL7909025A (en) | 1980-06-23 |
| FR2444666B1 (en) | 1982-11-12 |
| FI793964A (en) | 1980-06-20 |
| YU308479A (en) | 1983-12-31 |
| PL220531A1 (en) | 1980-08-25 |
| ES8100257A1 (en) | 1980-11-01 |
| GB2045744B (en) | 1982-11-10 |
| DD148216A5 (en) | 1981-05-13 |
| SU833157A3 (en) | 1981-05-23 |
| ATA765379A (en) | 1983-01-15 |
| GB2045744A (en) | 1980-11-05 |
| SE7910430L (en) | 1980-06-20 |
| CS209944B2 (en) | 1981-12-31 |
| AU5396779A (en) | 1980-06-26 |
| US4285942A (en) | 1981-08-25 |
| IT7928029A0 (en) | 1979-12-17 |
| AU530721B2 (en) | 1983-07-28 |
| CH647755A5 (en) | 1985-02-15 |
| CA1123852A (en) | 1982-05-18 |
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